Submissions for variant NM_004329.3(BMPR1A):c.478A>G (p.Met160Val)

gnomAD frequency: 0.00007  dbSNP: rs145101532

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129348	SCV000184112	benign	Hereditary cancer-predisposing syndrome	2022-09-16	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205803	SCV000259496	uncertain significance	Juvenile polyposis syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 160 of the BMPR1A protein (p.Met160Val). This variant is present in population databases (rs145101532, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 141022). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000656783	SCV000564703	uncertain significance	not provided	2020-12-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with personal or family history of colon or other cancers (Cabanillas 2017, Mandelker 2017, Yurgelun 2017); This variant is associated with the following publications: (PMID: 28873162, 28135145, 28717660)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656783	SCV000600225	likely benign	not provided	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129348	SCV000682896	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 160 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer in the literature (PMID: 28135145). This variant has been identified in 17/282744 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002478385	SCV000894556	uncertain significance	Polyposis syndrome, hereditary mixed, 2; Juvenile polyposis syndrome	2022-01-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129348	SCV002528603	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-05	criteria provided, single submitter	curation
Breakthrough Genomics, Breakthrough Genomics	RCV000656783	SCV005190902	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003894991	SCV004712211	uncertain significance	BMPR1A-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The BMPR1A c.478A>G variant is predicted to result in the amino acid substitution p.Met160Val. This variant has been reported in individuals with different cancer types, including colorectal cancer and leukemia (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Supplementary Table 4a, Zhang et al. 2015. PubMed ID: 26580448; eTable, Mandelker et al. 2017. PubMed ID: 28873162). It has also been reported in healthy controls (Okawa et al. 2023. PubMed ID: 36243179). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-88659831-A-G). It has conflicting classifications listed in ClinVar, ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141022/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.